Clinical Diagnosis

The clinical features of Feingold syndrome 1 (FS1) have been reviewed by Marcelis et al [2008]. Major features:

• Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly)
• Microcephaly (occipito-frontal circumference <10th centile)
• Short palpebral fissures
• Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI).

A diagnosis of FS1 can be made when a MYCN mutation or deletion is identified. In the absence of a MYCN abnormality a clinical diagnosis of FS1 should still be considered in the presence of typical digital anomalies with microcephaly or gastrointestinal atresia or typical facial features.

Molecular Genetic Testing

Gene. MYCN is the only gene in which mutations are known to cause Feingold syndrome 1 [van Bokhoven et al 2005]

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Feingold Syndrome 1

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
MYCN 2	Sequence analysis	Sequence variants 3	65% 4	Clinical
	Deletion / duplication testing 5	Exonic and partial-gene deletions	10% 6

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Typical digital anomalies were absent in individuals with FS1 in whom no MYCN mutation was identified [Marcelis et al 2008], whereas these typical digital anomalies are present in more than 95% of individuals with FS1 who have MYCN mutations.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Sequence analysis of all three exons of MYCN detected mutations in 65% of individuals/families with a clinical suspicion of Feingold syndrome 1 [Marcelis et al 2008].

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

6. Deletion/duplication testing detects mutations in 10% of individuals/families with Feingold syndrome 1 [Marcelis et al 2008].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

Confirming/establishing the diagnosis in a proband

• When a diagnosis of FS1 is suspected, molecular testing can begin with sequence analysis of MYCN.
• If no sequence variant is identified, additional deletion/duplication analysis can be performed.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with (germline) mutations in MYCN.

Note: Somatic amplification of human N-Myc, now formally denoted as MYCN, is associated with poor prognosis in neuroblastoma and can be found in approximately 25% of all cases [Lu et al 2003].

Natural History

Feingold syndrome 1 (FS1) as described by Feingold [1975] and Brunner & Winter [1991] is characterized by digital anomalies, microcephaly, facial dysmorphism, gastrointestinal atresias, and learning disability. The features are summarized in Table 2.

The most consistent findings are digital anomalies. Brachymesophalangy (shortening of the 2nd and 5th middle phalanx of the hand with clinodactyly of the 5th finger) has been present in 100% of individuals reported to have a MYCN mutation. Toe syndactyly (2-3 and/or 4-5) has been reported in 97%. Thumb hypoplasia is also common. See Figures 1, 2, and 3.

Figure

Figure 1. Typical brachymesophalangy in an adult with FS1

Figure

Figure 2. X-ray showing typical brachymesophalangy (digits 2 and 5) and thumb hypoplasia

Figure

Figure 3. Typical syndactyly of 2nd and 3rd or 4th and 5th toe

Gastrointestinal atresia (esophageal and/or duodenal) is a cause of major medical concern in FS1 and requires immediate surgical intervention (see Management). Cardiovascular and renal malformations are seldom severe in FS1.

Mild learning deficit is frequent in FS1. Clear intellectual disability is rare but intelligence is below average when compared to the general population and healthy, unaffected family members.

Some reports show that growth is impaired in FS1 [Shaw-Smith et al 2005]. Obvious short stature (height <3rd centile) is uncommon but average is decreased compared to the general population.

Associated features that occur in fewer than 50% of affected individuals include renal and cardiac abnormalities and hearing loss.

Genotype-Phenotype Correlations

No significant differences are observed among individuals with deletions or missense, nonsense, or frameshift mutations.

Penetrance

The penetrance for major features of FS1, especially digital abnormalities, seems to be 100% but clinical expression can vary considerably.

Nomenclature

Terms used in the past for Feingold syndrome1:

• Microcephaly-oculo-digito-esophageal-duodenal syndrome
• Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
• Microcephaly-digital anomalies-normal intelligence syndrome

Prevalence

Prevalence is unknown; FS1 is likely rare.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Feingold syndrome 1 (FS1), the following evaluations are recommended:

• Cardiac investigation (echocardiogram)
• Renal ultrasound to evaluate for structural abnormalities
• Audiometry for the possibility of hearing loss
• Neuropsychological evaluation if there are concerns about psychomotor development
• Analysis of the family pedigree for other possible affected individuals
• Medical genetics consultation

Treatment of Manifestations

Appropriate treatment includes the following:

• Surgical treatment of gastrointestinal atresia when present
• Follow up and treatment of possible cardiac and renal anomalies
• Treatment for significant hearing loss
• Developmental or educational intervention for children with learning difficulties

Prevention of Secondary Complications

Prophylactic antibiotics may be needed when cardiac or renal anomalies are present.

Surveillance

Routine follow up for any of the above-listed medical issues by the appropriate specialist is warranted.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because of the risk for major congenital abnormalities of the gastrointestinal tract, heart, and kidney, high-resolution ultrasound investigations (including fetal echocardiogram) are advised in any pregnancy in which one of the parents is known to be affected.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Feingold syndrome 1 (FS1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals (~60%) diagnosed with FS1 have an affected parent.
• A proband with FS1 may have the disorder as the result of a new gene mutation. De novo mutations were observed in approximately 30% of FS1 cases [Marcelis et al 2008; Author, personal communication].
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical examination for the presence of FS1 features (digital anomalies, microcephaly, and facial features). If a molecular diagnosis has been established in the proband, molecular testing of the parents is advised. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although many (~60%) individuals diagnosed with Feingold syndrome 1 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with FS1 has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Brunner HG, Winter RM. Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia. J Med Genet. 1991;28:389–94. [PMC free article: PMC1016903] [PubMed: 1870095]
2. Charron J, Gagnon JF, Cadrin-Girard JF. Identification of N-myc regulatory regions involved in embryonic expression. Pediatr Res. 2002;51:48–56. [PubMed: 11756639]
3. De Pontual L, Yao E, Callier P, Faivre L, Drouin V, Cariou S, van Haeringen A, Genevieve D, Goldenberg A, Oufadem M, Manouvrier S, Munnich A, Vidigal JA, Vekemans M, Lyonnet S, Henrion-Caude A, Ventura A, Amiel J. Germline deletion of the miR-17-92 cluster causes growth and skeletal defects in humans. Nat Genet. 2011;43:1026–30. [PMC free article: PMC3184212] [PubMed: 21892160]
4. Feingold M. Case Report 30. Synd Ident. 1975;3:16–17.
5. Jopling CL, Willis AE. N-myc translation is initiated via an internal ribosome entry segment that displays enhanced activity in neuronal cells. Oncogene. 2001;20:2664–70. [PubMed: 11420678]
6. Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002;16:2699–712. [PMC free article: PMC187459] [PubMed: 12381668]
7. Lu X, Pearson A, Lunec J. The MYCN oncoprotein as a drug development target. Cancer Lett. 2003;197:125–30. [PubMed: 12880971]
8. Marcelis CLM, Hol FA, Graham GE, Rieu PNMA, Kellermayer R, Meijer RPP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer APM. Genotype-Phenotype correlations in MYCN-Related Feingold syndrome. Human Mutation. 2008;29:1125–32. [PubMed: 18470948]
9. Ota S, Zhou ZQ, Keene DR, Knoepfler P, Hurlin PJ. Activities of N-Myc in the developing limb link control of skeletal size with digit separation. Development. 2007;134:1583–92. [PubMed: 17360777]
10. Shaw-Smith C, Willatt L, Thalange N. Growth deficiency in oculodigitoesophagoduodenal (Feingold) syndrome--case report and review of the literature. Clin Dysmorphol. 2005;14:155–8. [PubMed: 15930908]
11. van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B, van Beusekom E, Rieu P, Newbury-Ecob RA, Chiang C, Brunner HG. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat Genet. 2005;37:465–7. [PubMed: 15821734]

Revision History

• 6 September 2012 (me) Comprehensive update posted live
• 30 June 2009 (me) Review posted live
• 23 April 2009 (cm) Original submission